CN108373468A - A kind of preparation method of N-2- pyridines -5- pyrimetamines - Google Patents
A kind of preparation method of N-2- pyridines -5- pyrimetamines Download PDFInfo
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- CN108373468A CN108373468A CN201810479792.3A CN201810479792A CN108373468A CN 108373468 A CN108373468 A CN 108373468A CN 201810479792 A CN201810479792 A CN 201810479792A CN 108373468 A CN108373468 A CN 108373468A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to pesticide intermediate preparing technical fields, and in particular to a kind of preparation method of 2 pyridines of N, 5 pyrimetamine.The preparation method is to be reacted with 25% ammonium hydroxide using 3 ethyoxyl, 2 methacrolein cheap and easy to get as starting material, obtain 3 amino, 2 methacrolein；Then it is cyclized with formamide, obtains 5 methylpyrimidines；In carbon tetrachloride solution 5 bromomethyl pyrimidines are obtained with N bromosuccinimide brominations；Then under the action of triethylamine, 2 pyridines of N, 5 pyrimetamine is obtained by the reaction with 2 aminopyridines.The present invention is by devising completely new 2 pyridines of N, a 5 pyrimetamine preparation process route, and using 3 ethyoxyl, 2 methacrolein as starting material, by ammonification, cyclisation, bromination obtains 5 bromomethyl pyrimidines, purpose product then is obtained by the reaction with 2 aminopyridines；The present invention uses the cheap 3 ethoxy-c olefine aldehydrs that are easy to get, and compared to 5 expensive pyrimidinecarboxaldehydes are used in common process, greatly reduces the cost of production.
Description
Technical field
The invention belongs to pesticide intermediate preparing technical fields, and in particular to a kind of system of N-2- pyridines -5- pyrimetamines
Preparation Method.
Background technology
Trifluoro-benzene pyrimidine (triflumezopyrim) chemical name：2- hydroxyl -4- oxygen -1-5- Pyrimidylmethyl -3- [3-
(trifluoromethyl) phenyl] -4H-, chemical structural formula is：
Trifluoro-benzene pyrimidine (triflumezopyrim) is the novel mesoionic class or amphoteric ion insecticides of Du Pont's research and development
(mesoionic insecticides；Zwitterionic insecticides), also it is new pyrimidine ketone compounds.Its
Efficiently, holding effect, dosage are low, environmentally friendly, water rice hopper, leafhopper etc. are mainly prevented, to various pests such as Lepidoptera, Homopteras
Good preventive effect is all had, cotton, rice, corn and Soybean and Other Crops are can be used for.
The synthesis of trifluoro-benzene pyrimidine is double by N-2- pyridine -5- pyrimetamines and 2- [3- (trifluoromethyl) phenyl] malonic acid
(2,4,6- trichlorophenyl) ester in toluene solvant, is obtained by back flow reaction, and reaction process is as follows：
Wherein N-2- pyridines -5- pyrimetamines are the key intermediates for synthesizing trifluoro-benzene pyrimidine.Patent WO2012092115
It is reported using 5- pyrimidinecarboxaldehydes as raw material with WO 2013090547, reacts with 2- aminopyrimidines, then obtained through sodium borohydride reduction
To N-2- pyridine -5- pyrimetamines, there are two disadvantages for the route, first, 5- pyrimidinecarboxaldehydes are expensive, are not easy to obtain, second is that
Expensive sodium borohydride is used, and sodium borohydride reduction yield is relatively low.Its synthetic route is as follows：
Invention content
The present invention is in view of the deficiencies of the prior art, and it is an object of the present invention to provide a kind of system of new N-2- pyridine -5- pyrimetamines
Preparation Method.
For achieving the above object, the technical solution adopted by the present invention is：
A kind of preparation method of N-2- pyridines -5- pyrimetamines, includes the following steps：
(1) 3- ethyoxyls-methacrolein and ammonium hydroxide are subjected to aminating reaction and generate 3- amino-2-methyl methacrylaldehyde；
(2) under the effect of the catalyst, step (1) prepares gained 3- amino-2-methyls methacrylaldehyde and carries out ring with formamide
Change reaction and generates 5- methylpyrimidines；
(3) 5- methylpyrimidines are dissolved in solvent, bromating agent, initiator is added, it is phonetic to carry out bromination reaction generation 5- bromomethyls
Pyridine；
(4) 5- bromomethyls pyrimidine and 2-aminopyridine, acid binding agent and solvent are added in reaction bulb, heating is stirred to react
Generate N-2- pyridine -5- pyrimetamines.
In said program, the mass concentration of ammonium hydroxide described in step (1) is 20~25%, the 3- ethyoxyls -2- methyl
The molar ratio of methacrylaldehyde and ammonia is 1:1.0~1.5:1.0~6.0；10~25 DEG C of the temperature of the aminating reaction, the time be 1~
10h；The yield of the reaction is 80~90%.
In said program, 3- amino-2-methyls methacrylaldehyde carries out cyclization with formamide and generates 5- methyl in step (2)
The reaction step of pyrimidine is as follows：3- amino-2-methyls methacrylaldehyde, formamide and catalyst are added in reaction bulb, heating adds
Heat carries out cyclization, after reaction, cooling, is poured into water, and with chloroform extraction, washes, concentrates, is evaporated under reduced pressure, should
The yield 85~90% of reaction；
The molar ratio of the 3- amino-2-methyls methacrylaldehyde and formamide is 1:1~1.5；
The catalyst is one kind in pyridine hydrochloride, pyridine acetic acid salt, piperidine hydrochlorate and piperidines acetate, described
The dosage of catalyst is the 1%~10% of the amount of 3- amino-2-methyl methacrylaldehyde substances.
The reaction temperature of the cyclization is 100~140 DEG C, and the reaction time is 5~10h.
In said program, 5- methylpyrimidines carry out bromination reaction with bromating agent and generate 5- bromomethyl pyrimidines in step (3)
Reaction step is as follows：Equipped with blender, 5- methylpyrimidines, solvent are added in four mouthfuls of reaction bulbs of thermometer and reflux condensing tube
And initiator, heating, bromating agent is added, bromination reaction is carried out under counterflow condition；After reaction, it is cooled to room temperature, is washed with water
It washs, concentrates, residual night vacuum distillation, the yield 55~75% of the reaction；
The solvent is carbon tetrachloride, chloroform, dichloromethane or dichloroethanes；
The bromating agent is N-bromosuccinimide, bromine or hydrogen bromide/hydrogen peroxide；
The initiator can be azo isobutyronitrile or perbenzoic acid；
The molar ratio of the 5- methylpyrimidines and bromating agent is 1:1~1.5；
The reaction temperature of the bromination reaction is 50~60 DEG C, and the reaction time is 2~10h.
5- bromomethyls pyrimidine is reacted with 2-aminopyridine in said program, in step (4) generates N-2- pyridine -5- pyrimidine first
The reaction step of amine is as follows：5- bromomethyls pyrimidine and 2-aminopyridine, acid-capture agent and solvent are added in reaction bulb, heating is stirred
Mix reaction；It is cooling, reaction solution is poured into water, organic layer is separated, water layer is extracted with toluene, merges organic phase, and washing and drying is dense
It contracts dry that pale yellow oil, cold cold crystallization obtain faint yellow solid；The yield 76~80% of the reaction；
The molar ratio of the 5- bromomethyls pyrimidine and 2-aminopyridine is 1:1~1.5.
The reaction temperature being stirred to react that heats up is 115~120 DEG C, and the reaction time is 2~10h.
The acid binding agent is pyridine, triethylamine, sodium bicarbonate or saleratus；
The solvent is dimethylbenzene, toluene, carbon tetrachloride, chloroform, dichloromethane or dichloroethanes.
The preparation method of -5 pyrimetamine of N-2- pyridines of the present invention includes：Reaction equation is as follows：
Beneficial effects of the present invention are as follows：The present invention is prepared by devising completely new -5 pyrimetamine of N-2- pyridines
Process route, using 3- ethyoxyls-methacrolein as starting material, by ammonification, cyclisation, it is phonetic that bromination obtains 5- bromomethyls
Then purpose product is obtained by the reaction with 2-aminopyridine in pyridine；The present invention uses the cheap 3- ethoxy-c olefine aldehydrs that are easy to get, and compares
Using expensive 5- pyrimidinecarboxaldehydes in common process, the cost of production is greatly reduced；Preparation method tool of the present invention simultaneously
There is the advantages of high income.
Specific implementation mode
For a better understanding of the present invention, with reference to the embodiment content that the present invention is furture elucidated, but the present invention
Content is not limited solely to the following examples.
Embodiment 1
A kind of preparation method of N-2- pyridines -5- pyrimetamines, includes the following steps：
(1) synthesis of 3- amino-2-methyls methacrylaldehyde：114g (1.0mol) 3- ethyoxyl -2- alkyl aldehyde is added
It is cooled down with ice brine in blender and thermometer 500ml reaction bulbs, is used in, 25% ammonium hydroxide is added dropwise at 0~10 DEG C
750ml, 1~2h of time for adding after being added dropwise, are to slowly warm up to 25 DEG C, and solution is yellow, the reaction was continued 2~3h；Then subtract
Concentrated reaction mixture is pressed, has the precipitation of 3- amino methacrylaldehyde crystal, with recrystallizing to obtain 76.5 solids, yield in ethyl acetate
90%, fusing point fusing point：113-114℃；
(2) synthesis of 5- methylpyrimidines：By 85.0g (1.0mol) 3- amino -2- alkyl aldehyde, 54g (1.2mol) first
Amide and 2.0g acetic acid piperidinium salts, which are added, carries blender, in reflux condensing tube and thermometer 500ml reaction bulbs, is warming up to 125
DEG C, the reaction was continued 12~14h；It then cools to room temperature, is extracted with chloroform, washed, magnesium sulfate drying, concentration；Vacuum distillation is received
Collect the fraction 82.7g of 65~66 DEG C/10mmHg, yield 88%；
(3) the phonetic synthesis of 5- bromomethyls：94.0g (1.0mol) 5- picolines are dissolved in the carbon tetrachloride solution of 500ml
In, 2.g 2 is added, 2- azo isobutyronitriles are heated to reflux, and N-bromosuccinimide 195.8g is then added portionwise
(1.1mol), addition finishes that the reaction was continued 2~4h are then cooled to room temperature；Filtering, filtrate water washing, magnesium sulfate drying are dense
Contracting；The fraction 120.4g of 65~66 DEG C/10mmHg, yield 70%, 1H NMR (CDCl3) are collected in vacuum distillation：δ 4.40 (s,
2H), 8.79 (s, 2H), 9.16 (s, 1H)；
(4) synthesis of the synthesis of -5 pyrimetamine of N-2- pyridines：Equipped with blender, thermometer, the 500mL tetra- of condenser pipe
In mouth reaction bulb, 137.6g (0.8mol) 5- bromomethyl pyrimidines, 77.1g (0.82mol) 2-aminopyridine and 300mlN, N- is added
Dimethylformamide is added dropwise 85.5g (0.85mol) triethylamine, is added dropwise at room temperature, is warming up to 60 DEG C, reacts 7~8h,
Decompression steams most of solvent, then pours into ice water residual night, is extracted with dichloromethane, washes, anhydrous magnesium sulfate drying；It is dense
Contracting, residual ight ethyl alcohol recrystallization obtain faint yellow solid 110.4g, yield 75%.1H NMR(CDCl3)：δ 4.61 (d, 2H),
4.96 (brs, NH), 6.43 (d, 1H), 6.65 (t, 1H), 7.42 (t, 1H), 8.12 (d, 1H), 8.75 (s, 2H), 9.10 (s,
1H)。
Embodiment 2
A kind of preparation method of N-2- pyridines -5- pyrimetamines, includes the following steps：
(1) with embodiment 1；
(2) with embodiment 1；
(3) the phonetic synthesis of 5- bromomethyls：94.0g (1.0mol) 5- picolines are dissolved in the carbon tetrachloride solution of 500ml
In, 2.g 2 is added, 2- azo isobutyronitriles are heated to reflux, and are then added dropwise bromine 176g (1.1mol), and addition finishes that the reaction was continued 2
~4h；It then cools to room temperature, filters, filtrate is washed with sodium sulfite aqueous solution, magnesium sulfate drying, concentration.Vacuum distillation is received
Collect the fraction 111.8g of 65-66 DEG C/10mmHg, yield 65%, 1H NMR (CDCl3)：δ 4.40 (s, 2H), 8.79 (s, 2H),
9.16 (s, 1H).
(4) synthesis of the synthesis of -5 pyrimetamine of N-2- pyridines：Equipped with blender, thermometer, the 500mL of condenser pipe
In four mouthfuls of reaction bulbs, 137.6g (0.8mol) 5- bromomethyl pyrimidines, 77.1g (0.82mol) 2-aminopyridine is added
85.0g (0.85mol) saleratus is added dropwise, is added dropwise, is warming up to 80 at room temperature with 300mlN- methyl pyrrolidones
DEG C, 3~4h is reacted, and decompression steams most of solvent, then residual night is poured into ice water, is extracted with dichloromethane, washes, anhydrous
Magnesium sulfate is dried, and concentration, residual ight ethyl alcohol recrystallization obtains faint yellow solid 119.4g, yield 80%.1H NMR(CDCl3)：δ
4.61 (d, 2H), 4.96 (brs, NH), 6.43 (d, 1H), 6.65 (t, 1H), 7.42 (t, 1H), 8.12 (d, 1H), 8.75 (s,
2H), 9.10 (s, 1H).
Obviously, above-described embodiment be only intended to clearly illustrate made by example, and not limitation to embodiment.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And the obvious variation or change therefore amplified
The dynamic protection domain still in the invention it.
Claims (9)
1. a kind of preparation method of N-2- pyridines -5- pyrimetamines, which is characterized in that include the following steps：
（1）3- ethyoxyls-methacrolein and ammonium hydroxide are subjected to aminating reaction and generate 3- amino-2-methyl methacrylaldehyde；
（2）Under the effect of the catalyst, by step（1）Gained 3- amino-2-methyls methacrylaldehyde is prepared to be cyclized with formamide
Reaction generates 5- methylpyrimidines；
（3）5- methylpyrimidines are dissolved in solvent, bromating agent, initiator is added, bromination reaction occurs and generates 5- bromomethyl pyrimidines；
（4）5- bromomethyls pyrimidine and 2-aminopyridine, acid binding agent and solvent are added in reaction bulb, heating is stirred to react generation
N-2- pyridine -5- pyrimetamines.
2. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（1）Middle institute
The mass concentration for stating ammonium hydroxide is 20 ~ 25%, and the molar ratio of the 3- ethyoxyls-methacrolein and ammonia is 1:1.0~1.5:
1.0~6.0。
3. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（1）Middle institute
10 ~ 25 DEG C of the reaction temperature of aminating reaction is stated, the reaction time is 1 ~ 10h.
4. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（2）Middle institute
It is one kind in pyridine hydrochloride, pyridine acetic acid salt, piperidine hydrochlorate and piperidines acetate, the use of the catalyst to state catalyst
Amount is the 1% ~ 10% of the amount of 3- amino-2-methyl methacrylaldehyde substances.
5. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（2）Middle institute
The molar ratio for stating 3- amino-2-methyls methacrylaldehyde and formamide is 1:1~1.5；The reaction temperature of the cyclization be 100 ~
140 DEG C, the reaction time is 5 ~ 10h.
6. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（3）Middle institute
It is carbon tetrachloride, chloroform, dichloromethane or dichloroethanes to state solvent；The bromating agent be N-bromosuccinimide, bromine,
Or hydrogen bromide/hydrogen peroxide；The initiator can be azo isobutyronitrile or perbenzoic acid.
7. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（3）Middle institute
The molar ratio for stating 5- methylpyrimidines and bromating agent is 1:1~1.5；The reaction temperature of the bromination reaction is 50 ~ 60 DEG C, when reaction
Between be 2 ~ 10h.
8. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（4）Middle institute
It is pyridine, triethylamine, sodium bicarbonate or saleratus to state acid binding agent；The solvent is dimethylbenzene, toluene, carbon tetrachloride, chlorine
Imitative, dichloromethane or dichloroethanes.
9. the preparation method of N-2- pyridines -5- pyrimetamines according to claim 1, which is characterized in that step（4）Middle institute
The molar ratio for stating 5- bromomethyls pyrimidine and 2-aminopyridine is 1:1~1.5；The reaction temperature of the reaction is 115 ~ 120 DEG C, instead
It is 2 ~ 10h between seasonable.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020952A (en) * | 2018-11-01 | 2018-12-18 | 雅本化学股份有限公司 | A kind of preparation method of N-2- pyridyl group -5- pyrimetamine |
| CN112707888A (en) * | 2021-02-03 | 2021-04-27 | 上海雅本化学有限公司 | Synthesis method of N-2-pyridyl 5-pyrimidyl methylamine |
| WO2023086802A1 (en) * | 2021-11-10 | 2023-05-19 | Corteva Agriscience Llc | Processes for the preparation of certain mesoionic pesticides |
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| CN103459387A (en) * | 2010-12-29 | 2013-12-18 | 杜邦公司 | Mesoionic pyrido [1,2 -A] pyrimidine pesticides |
| CN104066713A (en) * | 2011-12-15 | 2014-09-24 | 纳幕尔杜邦公司 | Malonic acid di-salts and a method for preparing malonyl dihalides |
| WO2017189339A1 (en) * | 2016-04-26 | 2017-11-02 | E I Du Pont De Nemours And Company | Process for the preparation of n-[(5-pyrimidinyl)methyl]-2-pyridinamines |
-
2018
- 2018-05-18 CN CN201810479792.3A patent/CN108373468B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103459387A (en) * | 2010-12-29 | 2013-12-18 | 杜邦公司 | Mesoionic pyrido [1,2 -A] pyrimidine pesticides |
| CN104066713A (en) * | 2011-12-15 | 2014-09-24 | 纳幕尔杜邦公司 | Malonic acid di-salts and a method for preparing malonyl dihalides |
| WO2017189339A1 (en) * | 2016-04-26 | 2017-11-02 | E I Du Pont De Nemours And Company | Process for the preparation of n-[(5-pyrimidinyl)methyl]-2-pyridinamines |
Non-Patent Citations (1)
| Title |
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| WENMING ZHANG等: "Mesoionic pyrido[1,2-a]pyrimidinones:Discovery of triflumezopyrim as a potent hopper insecticide", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109020952A (en) * | 2018-11-01 | 2018-12-18 | 雅本化学股份有限公司 | A kind of preparation method of N-2- pyridyl group -5- pyrimetamine |
| CN112707888A (en) * | 2021-02-03 | 2021-04-27 | 上海雅本化学有限公司 | Synthesis method of N-2-pyridyl 5-pyrimidyl methylamine |
| WO2023086802A1 (en) * | 2021-11-10 | 2023-05-19 | Corteva Agriscience Llc | Processes for the preparation of certain mesoionic pesticides |
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